Clinical pharmacology of cancer chemotherapy in children

The pharmacokinetics of most anticancer drugs are highly variable in children, and are commonly different when children are compared to adults. Several recent studies have demonstrated that variability in systemic exposure due to interpatient pharmacokinetic variability, may be related to the probability of oncolytic effects or toxicity for some anticancer drugs. This review has exemplified differences in the clinical pharmacology of several anticancer drugs, when children are compared to adults. Such age-related differences in the pharmacokinetics and pharmacodynamics of these drugs, together with biologic differences between pediatric and adult cancers, provide the rationale for systematically conducting pediatric phase I through IV studies of anticancer drugs and denote the risks of relying on adult trials to identify new therapeutic strategies for childhood cancers.     

Clinical practice treatment of HIV infection in children

Perinatal transmission remains the main cause of HIV infection in the pediatric population. Treatment of HIV-infected children has become less of a problem in resource-rich countries with a remarkable decrease of perinatal infections, resulting in an effective prevention of mother-to-child transmission and antiretroviral treatment of HIV infection in pediatrics because of differences in drug pharmacokinetics, the lack of available licensed drugs, the use of different immunologic markers and age-related adherence issues. This review, for the general pediatrician, summarizes the most recent pediatric data and guidelines for treatment of HIV. Recommendations for when to initiate therapy are more aggressive in children than in adults, particularly in infants because disease progression in children is more rapid. The indications to start therapy differ by age and are based on international immunologic and clinical classification system for HIV infection. At present, combination regimens of at least three drugs are recommended. Moreover, therapies must also consider the potential complications in these children currently treated for a long time.     

Peculiarities of drug therapy in childhood

The age of the patient is one of the major determinants of drug efficacy due to certain anatomical, physiological, biochemical and behavioral characteristics of different age groups of the pediatric population. Qualitative and quantitative differences in pharmacokinetics and pharmacodynamics of drugs should be considered before dosage regimens can be established. Differences may occur in each age group, but may be even greater in newborns. Nevertheless, the maturation from the newborn towards adulthood proceeds through a continuum and thus involves also other age groups. Pediatricians are aware of this situation. But only for a small fraction of drugs used in newborns and infants clinical-pharmacological data are available, and drug instructions often contain disclaimer statements against the use in children. In pediatric intensive care units newborns and infants often receive drugs which have not been evaluated before within this age group. According to epidemiological data it has to be assumed that 30% of neonates in neonatal care units develop adverse side effects, which may originate from the drug itself or from drug interactions. Drug trials are completed or underway when new approaches to therapeutic interventions are developed for pediatric disease states. Examples for the development of new therapeutic interventions are for instance the use of theophylline for the prevention of apnoes in prematures, the use of indomethacin for the closure of a patent ductus arteriosus, or the specific advances of cancer chemotherapy in childhood. However, there is no doubt that a complete interplay between clinical, ethical and legal aspects renders the task of studying the effects of drugs in children more difficult than in the case of adults.     

Pharmacology of inotropic agents in infants and children

Inotropic agents are drugs which increase the stroke work of the heart at a given pre-load and after-load. All of these agents work through a final common pathway involving the modulation of calcium interactions with various myocardial contractile proteins. The agents employed with pediatric patients include the cardial glycosides, catecholamine beta-agonists and the selective phosphodiesterase III inhibitors. Digoxin is the prototypic cardiac glycoside which has a long history of safe and effective use in infants and children. Its utility in improving right ventricular dysfunction in patients with cor pulmonale leading to biventricular dysfunction makes it ideally suited to the pediatric population. Monitoring digoxin pharmacokinetics in infants is confounded by the presence of an endogenous digoxin-like substance. Nevertheless, the drug is well suited for subacute and chronic myocardial support. In contrast, the catecholamines are the drugs of choice for acute intervention. Their pharmacokinetics permit rapid dosing titration. In infants and children the greatest experience has been accrued with dopamine, a mixed alpha- and beta-agonist but both epinephreine and norepinephrine are being used with increasing frequency as the need for drugs with increased potency and pressor activity becomes more common. The phosphodiesterase inhibitors amrinone and milrinone are the newest additions to our therapeutic armamentarium. In addition to their modest inotropic effects, amrinone and to a greater extent, milrinone offer significant pulmonary vasodilatation as part of their therapeutic package. These effects occur with little or any impact on myocardial oxygen consumpton while their lusitropic effects enhance relaxation in hypertrophied ventricular muscle. Of the two agents milrinone is probably preferred due to its greater therapeutic index and shorter elimination half-life. All of these agents remain important tools in the care of critically ill infants and children. The rational use of these drugs based upon their pharmacokinetic and pharmacodynamic properties is essential to achieve their optimal effects.     

Targeted therapy: for kids, too

Innovative hypothesis-driven clinical trials have achieved major successes over the past several decades in treating children and adolescents with cancer. DNA-damaging cytotoxic agents have cured children with cancer. While the mission is not yet accomplished, chemotherapy has been validated. None of these drugs were designed specifically for a pediatric disease. Continued progress will require new strategies. Now being tested for adult cancers, these strategies include gene therapy, immunotherapy, cancer prevention, and signal transduction inhibitor (STI) therapy. Of these, the most promising is STI therapy, also known as molecular therapeutics or targeted therapy. For this therapy to succeed, components of signal transduction (i.e., candidate drug targets) must be identified, the targets relevant to cancers, and the drugs available for trial. Because STI therapy is biologically driven and because therapy will be tailored depending on the molecular profile of a specific patient's tumor, clinical pediatric oncologists will need to acquire greater understanding of signaling pathways and their therapeutic relevance. With examples drawn from pediatric oncology, the critical steps in the pre-clinical development of targeted therapy are reviewed here.     

Micafungin: A brief review of pharmacology,safety, and antifungal efficacy in pediatric patients

Invasive fungal infections are a major cause of morbidity and mortality in children with hematological malignancies and those undergoing allogeneic hematopoietic stem‐cell transplantation (HSCT). Although several new antifungal compounds recently became available, some are not yet approved for the use in the pediatric population. Among the new class of echinocandins, micafungin has been licensed in Europe and Japan for children including neonates. Because micafungin is well tolerated and exhibits few clinical relevant drug–drug interactions, the compound is of particular interest for prophylaxis and treatment of invasive mycoses in pediatric patients with cancer or following allogeneic HSCT. This review will focus on the currently available pediatric data of micafungin with emphasis on pharmacokinetics, efficacy, and safety. Pediatr Blood Cancer. 2010;55:229–232. © 2010 Wiley–Liss, Inc.     

New agents for invasive mycoses in children

PURPOSE OF REVIEW: Invasive fungal infections are an important cause of morbidity and mortality in immunocompromised children of all ages. This review summarizes information on new antifungal agents, including current data on their clinical use in children, as well as alternative strategies such as antifungal combination and immunomodulation therapy. RECENT FINDINGS: Novel antifungal agents, such as the echinocandins and the second-generation triazoles, were recently introduced that exhibit promising efficacy against Candida spp., Aspergillus spp., and other opportunistic fungal pathogens. These compounds are generally well tolerated and show substantial efficacy as salvage treatment and equal or even superior efficacy compared with older azoles or amphotericin B as first-line or empiric therapy for fungal infections. Clinical studies of pharmacokinetics and efficacy of the new agents in the pediatric population are, however, limited. SUMMARY: The response rates observed with the recently introduced drugs, although superior in some cases compared with older antifungal agents, are still far from satisfactory. The development of new antifungal compounds as well as the use of alternative approaches of combination therapy and immunomodulation should be pursued through well-designed laboratory and clinical studies in pediatric patients.     

A new generation of anticonvulsants for the treatment of epilepsy in children

Over the past 12 years, a number of new anticonvulsant drugs have been introduced for the treatment of childhood epilepsy. The present article reviews these new agents and provides the considerations one should use in selecting an antiepileptic drug for use in children. While in some cases the newer antiepileptic drugs have a more favourable pharmacokinetic and toxicity profile than the older drugs, there appears to be no objective evidence that any currently available antiepileptic drug is superior in terms of therapeutic efficacy.     

Newer drugs in pediatric anesthesia

Recent developments in pharmacology have offered new and broader options to the anesthesiologist caring for pediatric patients. Many new drugs do not have specific indications for use in the pediatric population, but clinical studies have examined the utility and cost-effectiveness of some of these agents. Information is presented on drugs used for premedication, induction, and maintenance of anesthesia. The clinical pharmacology of several new nondepolarizing muscle relaxants, and the recent controversy with regard to the use of succinylcholine also are presented. New drugs used in topical and regional anesthesia as well as options for anti-emetic therapy are discussed.     

New targets and targeted drugs for the treatment of cancer: an outlook to pediatric oncology

Novel drugs and treatment modalities are urgently needed to further improve survival of children with cancer. In medical oncology, an increased understanding of the molecular basis of cancer is driving the development of new drugs that target relevant signaling pathways in cancer cells and tumor microenvironment. Small-molecule modulators of signal transduction and monoclonal antibodies against various cellular targets have been approved in adult cancers in recent years. These drugs are now starting to be considered for the use in children. Despite the biological differences between adult and pediatric cancers, common cellular pathways have emerged from experimental research. Thus, insights into clinical experience with molecular targeted drugs in adults may help to accelerate progress in pediatric oncology. Here, the authors review molecules and pathways for which drugs are approved for adult cancer treatment and provide links to existing and potential applications in pediatric oncology.     

Targeted MRI contrast agents for pediatric hepatobiliary disease

New options are available for the magnetic resonance imaging (MRI) assessment of pediatric hepatobiliary disease. This article describes the potential utility for MRI with contrast agents tailored for hepatobiliary imaging. MRI contrast agents that preferentially target the liver may be helpful in characterizing liver masses and bile duct abnormalities in select children. The imaging approach is noninvasive and relatively rapid to perform. It also provides anatomic and functional information and is a radiation-free alternative to other imaging strategies. This relatively new imaging procedure is placed in the context of more established imaging modalities. The pharmacokinetics, technical considerations, and potential applications of these hepatobiliary-specific contrast agents also are discussed.     

Antiviral therapies in children: has their time arrived?

The increase in the number and classes of antiviral agents that has occurred since the 1980s is remarkable. The rapid expansion in therapeutic options for previously untreatable illnesses challenges clinicians to gain familiarity and experience with these new drugs, especially with regard to their use in children. This article describes the clinical utilities, pharmacokinetics, and adverse effects of these new drugs to empower practitioners to use them appropriately.     

Stimulation programs for pediatric drug research – do children really benefit?

Most drugs that are currently prescribed in pediatrics have not been tested in children. Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act (FDAMA) that grants patent extensions when pediatric labeling is provided. We investigated the effectiveness of these programs in stimulating drug research in children, thereby increasing the evidence for safe and effective drug use in the pediatric population. All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or, if these were unavailable, the labeling information as provided by the manufacturer. A systematic search of the literature was performed to identify drug utilization patterns in children. From July 1998 to August 2006, 135 drug entities were granted pediatric exclusivity. Most frequent drug groups were anti-depressants and mood stabilizers, ACE inhibitors, lipid-lowering preparations, HIV antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs. The distribution of the different drugs closely matched the distribution of these drugs over the adult market, and not the drug utilization by children. Many drug studies in children have been performed since the introduction of the FDAMA. However, children infrequently use the drugs granted pediatric exclusivity. The priorities for pediatric drug research should be set by the need of the patients, not by market considerations. In memory of Isabelle Boots, the primary contributor to this work, who unexpectedly passed away at the brink of a promising career.     

Principles of pharmacology

An understanding of the basic principles of pharmacokinetics and pharmacodynamics of drugs is important in appropriate therapeutic use of various drugs. In simple terms, the effects of the body on the drug once it has entered the body has been referred to as pharmacokinetics, and it aims to provide a quantitative assessment of the main processes involved in biodisposition of the drug, including absorption, distribution, metabolism, and elimination. Pharmacodynamics concerns itself with the effects of the drug on the body and the main processes involved are the action of the drug on specific sites, especially the receptors. In addition, pharmacogenetics and pharmacogenomics evaluates the influence of genetics on drug response. This article reviews basic concepts of pharmacology applicable to psychotherapeutic agents used for the treatment of mental disorders of children and adolescents.     

New challenges in therapeutic management of human immunodeficiency virus-infected children]

More than 2 millions of children worldwide are HIV-infected. Recently, the HIV related mortality and morbidity has dramatically decreased due to the use of antiretroviral multitherapies in the HIV-infected children. However the therapeutic management of HIV-infected children is complex and may be complicated by socio-familial issues. Short and long term toxicity of antiretrovirals but also of HIV itself are of concern. Despite the good clinical and immunological results of antiretroviral multitherapies, virological failure may occur. Paediatric pharmacokinetic specificities and inadequate galenic presentation of drugs could lead to virological failure. However, the use of more potent drugs with more adapted presentation actually reduces this risk of failure. Prospective cohorts of HIV-infected children and new antiretroviral drugs paediatric evaluation are of key importance and can improve the paediatric therapeutic management. Finally, universal access to antiretroviral drugs in children, particularly in developing countries is the major actual and future challenge.     

What's new in pediatric pharmacology?]

Only a minority of the drugs administered to children and infants have a pediatric labeling and have been sufficiently tested for efficacy, safety and correct pediatric dosing, which cannot necessarily be extrapolated from adult data. This situation is scientifically and ethically unacceptable. To address this problem, the suggestion is being made in several countries that more formal legal requirements should be introduced. In the United States, in 1997, a new legislation encouraged pharmaceutical companies to study medicines in children (for example, by offering the financial incentive of a six-month extension to patent exclusivity). However, there are undeniable difficulties in pediatric and neonatal studies. To minimize the risks of clinical investigation in children, appropriate methodologies should be used. New in vitro and in vivo methods are now available, taking into account pediatric characteristics.     

Quoi de neuf en pharmacologie pédiatrique ?Advances in pediatric pharmacology.

Only a minority of the drugs administered to children and infants have a pediatric labeling and have been sufficiently tested for efficacy, safety and correct pediatric dosing, which cannot necessarily be extrapolated from adult data. This situation is scientifically and ethically unacceptable. To address this problem, the suggestion is being made in several countries that more formal legal requirements should be introduced. In the United States, in 1997, a new legislation encouraged pharmaceutical companies to study medicines in children (for example, by offering the financial incentive of a six-month extension to patent exclusivity). However, there are undeniable difficulties in pediatric and neonatal studies. To minimize the risks of clinical investigation in children, appropriate methodologies should be used. New in vitro and in vivo methods are now available, taking into account pediatric characteristics.